PROJECT SUMMARY/ABSTRACT Tauopathies are age-related neurodegenerative diseases including Alzheimer's disease that are characterized by tau accumulation in the brain and progressive cognitive decline. How pathogenic tau in neurons triggers memory loss in tauopathy is not well understood. Normal cognitive processes such as learning and memory involve the modulation of synaptic strength by plasticity mechanisms in neuronal circuits of the brain. At hippocampal synapses, the induction of long-term potentiation (LTP) enhances actin polymerization in spines and recruits additional AMPA-type glutamate receptors (AMPARs) to the postsynaptic membrane which produces a sustained increase in synapse strength. Tauopathy mouse models with high levels of pathogenic tau have impaired LTP expression at hippocampal synapses which coincides with their Alzheimer's disease related memory loss. To investigate the role of abnormal tau acetylation in Alzheimer's disease we previously generated a transgenic mouse that expresses human tau with lysine-to-glutamine mutations to mimic the acetylation of two lysines on tau (tauKQ). We found that tauKQ-expressing mice had hippocampal LTP and memory deficits that were linked to the loss of a memory-associated protein called KIBRA in postsynaptic spines. KIBRA is a large scaffold protein with several functionally-distinct protein interaction domains which could modulate signaling complexes important for postsynaptic function. Our work suggests that tau triggers memory deficits in Alzheimer's disease by reducing the KIBRA-dependent signaling that is essential for LTP expression. In preliminary studies, we showed that the C-terminal domain of KIBRA (C-term KIBRA) is sufficient to restore postsynaptic AMPAR trafficking during LTP in cultured neurons expressing tauKQ. Moreover, lentivirus-based expression of C-term KIBRA in hippocampus rescued the LTP impairment in tauKQ mice. In Aim 1, we will examine whether C-term KIBRA expression restores tau-mediated LTP and memory deficits in two different transgenic mouse lines that exhibit distinct tau pathology. These experiments will be performed on tauKQ mice, that model the increased levels of acetylated tau observed in Alzheimer's disease, and PS19 mice that express human tau with the P301S mutation that causes frontotemporal dementia and develop neurofibrillary tangle-like tau pathology. In Aim 2 we will test the hypothesis that C-term KIBRA restores LTP through its interaction with postsynaptic proteins that regulate actin dynamics and AMPAR trafficking. In collaboration with Dr. Birgit Schilling, we propose to use mass spectrometry to identify proteins that bind to C-term KIBRA in hippocampal neurons of tauKQ and PS19 mice. Then we will investigate the role of these C-term KIBRA interacting proteins in LTP expression. These studies will add a new dimension to Alzheimer's disease research by highlighting the impact of restoring KIBRA-dependent signaling and LTP on the recovery of memory encoding. We anticipate that this work will stimulate the development of new strategies to treat memory loss in Alzheimer's disease.